Our main objectives for this proposal are as follows: (1) To study the effect of Ca2 ion and pH on the kinetics of radioactive long lasting local anesthetics and similar type drugs in desheathed nerve (toad and rabbit); the perineural sheath, and in muscle (frog sartorius and barnacle muscle); (2) to determine the relationship between Na ion extrusion K ion over O uptake and O2 consumption during the potassium stimulated hyperpolarization of rabbit vagus nerve as modified by Ca2 ion over O. Our research proposal is concerned with the interactions of calcium and long lasting tertiary amine local anesthetics in nerve. We wish to study the effects of external pH in relation to the pKa of the long lasting anesthetic or related type drugs, e.g., tetracaine, dibucaine, SKF 525-A, on the kinetics of radioactively labeled drug uptake binding and washout. Once these parameters are known we will study the effects of these drugs on 45Ca and 28Mg binding influx and efflux in nerve (toad sciatic, rabbit vagus nerve). Similar type studies concerning the competition between local anesthetics and calcium or magnesium binding to the sarcolemmal membrane of the single barnacle muscle fiber are also proposed. A second objective of our proposal is to study the effects of volatile anesthetics as well as local anesthetics on O2 uptake in relation to calcium or sodium transport in toad sciatic nerve and frog sartorius muscle, as modified by adenyl cyclase stimulating agents or phosphodiesterase inhibitors. The second objective is related to understanding some of the pharmacological action of these drugs and a possible relationship to malignant hyperthermia. The methods to be employed for these studies are radioactive tracer techniques for measuring the kinetics of 3H drug uptake or washout, 22Na, 45Ca, 28Mg flux and 42K influx and efflux in nerve and muscle. Oxygen consumption is to be measured with the O2 electrode and electrolytes by atomic absorption. Electrophysiological techniques will be employed in regard to measuring the monophasic compound action potential, and resting potential in nerve. In the case of the barnacle muscle fiber, internal electrodes will be used for following membrane potential and voltage clamp techniques will be used to follow current flows across the sarcolemmal membrane.